Timely Identification of Neonatal Hypoglycemia Martha E Lyon PhD, - - PowerPoint PPT Presentation

Timely Identification

• f Neonatal

Hypoglycemia

Martha E Lyon PhD, DABCC, FACB Department of Pathology & Lab Medicine Royal University Hospital Saskatoon, Saskatchewan

Disclosures

• Speaking Honoraria

– Radiometer – Nova Biomedical – Draeger – Roche (Canada) – Alere (Canada)

• Research Support (Reagents, Instrumentation, Travel)

– Nova Biomedical – Roche Diagnostics (Canada) – Radiometer – Instrumentation Laboratories (Canada)

 ALOL Biomedical Inc

 Clinical Laboratory Consulting Business

Objectives

 Review the definition and incidence of

neonatal hypoglycemia

 Describe why it is so important to identify

neonatal hypoglycemia in a timely manner

 Discuss pre-analytical errors associated

with the collection and handling of blood specimens that will affect the measurement of glucose

 Neonatal hypoglycemia was first described

in 1929

 “Carbohydrate metabolism of premature

infants” Am J Dis Child 1929:38;912-23

 The fetus

receives its entire supply of glucose (70% of its energy needs) from the maternal circulation via the placental transfer

 At birth, the

infant must supply its own glucose needs

Glucose

 Hypoglycemia in neonates, infants and

children is essentially always a problem with adapting to a “fasting” state

Glucose

 Biochemical

pathways that maintain “fuel” during fasting are important to understand causes

• f hypoglycemia

Gluconeogenesis Glycogenolysis Ketogenesis

Neonatal Hypoglycemia

• ….”is not a medical condition in itself but a feature of

illness or failure to adapt from the fetal state of continuous transplacental glucose consumption to the extrauterine pattern of intermittent nutrient supply”

Wight, 2006

Objective #1

 To review the definition and incidence of

neonatal hypoglycemia

Objective #2

 To describe why it is so important to

identify neonatal hypoglycemia in a timely manner

Objective #3

 To discuss pre-analytical errors associated with

the collection and handling of blood specimens that will affect the measurement of glucose

Objective 1: Definition of Neonatal Hypoglycemia

1.6 mmol/L (29 mg/dL) 2.2 mmol/L (40 mg/dL) 2.7 mmol/L (49 mg/dL) 2.0 mmol/L (36 mg/dL) 2.6 mmol/L (47 mg/dL)

• Definition of hypoglycemia in the newborn is

controversial because of a lack of significant correlation among plasma glucose concentration, clinical symptoms and long- term sequelae

Neonatal Hypoglycemia

• No widely accepted definition
• Required blood [glucose] will be dependent upon:
• Gestational age
• Size
• Energy requirements
• Clinical Condition
• [glucose] where neurodevelopmental damage

happens is variable (requires further investigation)

David Christiansen, Screening and Treatment of Neonatal Hypoglycemia, 2009. The Pas, Manitoba

Signs and Symptoms of Hypoglycemia

 Jitteriness  Irritability  Hypotonia  Lethargy  High-pitched cry  Hypothermia  Poor suck  Tachypnea  Cyanosis  Apnea  Seizures  Cardiac arrest

[Glucose]

Verklan & Walden (2004) as cited by Amy Bloomquist Neonatal Hypoglycemia

What happens to glucose levels in healthy full term infants (breast fed) after birth?

What happens to glucose levels in healthy full term infants (breast fed) after birth?

Time (hours) Glucose (mmol/L)

4 8 12 2 4 6 8

10th centile 50th centile 90th centile

Hoseth, 2000

Time (hours) Glucose (mmol/L)

12 24 36 48 60 72 84 96 2 4 6 8

10th centile 50th centile 90th centile

Neonatal Hypoglycemia

• Meta-analysis (term babies) Alkalay et al., Am J. Perinatology 2006: 23(2), 115-9
• 5th percentile [glucose]
• 1.6 mmol/L (29 mg/dL)(1-2 hr of life)
• 2.2 mmol/L (40 mg/dL)(3-48 hr of life)
• 2.7 mmol/L (49 mg/dL)(48-72 hr of life)
• World Health Organization

Paediatric Child Health 2004: 9(10), 723-9 (Canadian Pediatrics Society Fetus and Newborn Committee)

• < 2.6 mmol/L (47 mg/dL)
• At- risk infants lead to short & long term neurological

(imaging) changes

• “Significant hypoglycemia is not and can never

be defined as a single number that can be universally to every individual patient. Rather, it is characterized by a value(s) that is unique to each individual and varies with both their state of physiologic maturity and influence of pathology”

Cornblath et al., 2000

Operational Thresholds

• Represent “Action Values”
• do not represent either normal or

abnormal

• prompt either further testing and/or

treatment

• Operational threshold

Cornblath et al., Pediatrics 2000; 105(5), 1141-4

• Always treat if <2.0 mmol/L (36 mg/dL);
• desire [glucose] ≥ 2.6 mmol/L (46.8

mg/dL)

Incidence of Hypoglycemia

• Usually occurs in the first days of life
• Overall incidence = 1-5/1000 live births

Verklan & Walden (2004) as cited by Amy Bloomquist Neonatal Hypoglycemia

Incidence of neonatal hypoglycemia in babies identified as at risk

Harris DL, Weston PJ, Harding JE.

• J. Pediatrics 2012; 161(5): 787-91
• Infants (n=514) (tertiary hospital)

≥ 35 weeks gestation Identified at risk of hypoglycemia Blood [glucose] in the first 48 hrs of life

Incidence of neonatal hypoglycemia in babies identified as at risk

Harris DL, Weston PJ, Harding JE.

• J. Pediatrics 2012; 161(5): 787-91
• 51% babies (260/514) became hypoglycemic (< 2.6 mmol/L;

46.8 mg/dL)

• 19% (97/514) had severe hypoglycemia (≤ 2.0 mmol/L; 36

mg/dL)

• 19% (98/514) had more than 1 episode
• 81% (315/390) of the hypoglycemic episodes occurred in the

first 24 hours

Infants at Highest Risk for Hypoglycemia

 < 37 weeks gestation  Infant of a diabetic mother  Small for gestational age  Large for gestational age  Stressed/ill infants  Exposure to certain medications

 Treatment of preterm labor  Treatment of hypertension  Treatment of type 2 diabetes  Benxothiazide diuretics  Tricyclic antipressants in the 3rd trimester

Karlsen (2006) as cited by Amy Bloomquist Neonatal Hypoglycemia

At birth….

 “Fuel” requirements for the baby are

achieved through a balance of

 Exogenous sources (breast milk, formula)  Endogenous glucose production

(glycogenolysis, gluconeogenesis)

 Endogenous alternate fuels (ketones)

So ….why are we so concerned about glucose levels in the neonate? Objective 2

“Cerebral glucose utilization accounts for 90% of the neonate’s glucose consumption”

Verklan & Walden (2004). Core Curriculum for Neonatal Intensive Care Nurses

“ Compared with adults, infants have a higher brain to body weight ratio, resulting in higher glucose demand in relation to glucose production capacity”

Objective 3

Pre-analytical errors associated with the collection and handling of blood specimens that will affect the measurement of glucose

Glucose meter: 2.9 mmol/L (52 mg/dL)

Glucose meter: 2.9 mmol/L (52 mg/dL)

Blood Gas Analyzer:

3.2 mmol/L (58 mg/dL)

Glucose meter: 2.9 mmol/L (52 mg/dL)

Blood Gas Analyzer:

3.2 mmol/L (58 mg/dL)

Clinical Lab (plasma hexokinase): 2.2 mmol/L (40 mg/dL)

Factors that can influence the measurement of glucose

• Type of blood tube (green top or grey top)
• Specimen temperature (to ice or not?)
• Time it takes from specimen collection to processing

in the lab (ex vivo glycolysis)

• Capillary versus Venous specimens
• Interferences (Sugar Confusion)

Specimen Collection for Glucose Measurement

Heparin Tube Glycolytic Inhibitor Tube

Glucose Determinations in Plasma and Serum: Potential Error Related to Increased Hematocrit

Richard A. Sidebottom, Paul R. Williams, and Keith S. Kanarek Clinical Chemistry 1982 vol 28 pp. 190-2

A Decrement in glucose significantly greater in heparin-treated samples then in either NaF-treated

• r clotted samples, p<0.05. b Not measured. C Decrease in glucose significantly greater in the

heparin-treated samples than in the NaF-treated samples, p<0.05

1 2 4 6 Infants Heparin 101 ± 2 90 ± 5 78 ± 6 63 ± 10 48 ± 7a NaF 101 ± 2 93 ± 7 89 ± 6 88 ± 6 87 ± 6 Clotted serum 101 ± 2

b

90 ± 8 83 ± 7 80 ± 6 Adults Heparin 89 ± 4 83 ± 3 78 ± 3 67 ± 3c 57 ± 3a NaF 89 ± 4 82 ± 3 80 ± 3 77 ± 3 75 ± 4 Clotted serum 89 ± 4

b

81 ± 3 73 ± 4 70 ± 4

Table 2. Effect of Heparin, Fluoride, or No Anticoagulant on Glucose Values (mg/dL, mean ±SEM)

Time after blood collection, hours

Rebuilt from original

To ice or not to ice the blood specimen?

Effect of Cooling the Blood Specimens

Effect of time between specimen collection and specimen processing

Table 1. Glucose changes with Increasing Hematocrit (Hct) and Time (hours)

Please note: Specimens were collected into sodium heparin

Hct 0 hour 1 hour 2 hours 4 hours 6 hours Adult group 1 0.43 89 ± 4a 83 ± 3 78 ± 3 67 ± 3 57 ± 3 Adult group 2 0.51 89 ± 4 82 ± 3 76 ± 3 63 ± 2 52 ± 2 Infant group 1 0.51 101 ± 2 90 ± 5 78 ± 6 63 ± 10 48 ± 7 Adult group 3 0.60 89 ± 4 80 ± 3 73 ± 3 58 ± 3 42 ± 3 Infant group 2 0.60 101 ± 2 87 ± 4 73 ± 5b 58 ± 5b 36 ± 6b Adult group 4 0.68 89 ± 4 79 ± 3 70 ± 2 51 ± 2 31 ± 3 Infant group 3 0.71 101 ± 2 83 ± 5 66 ± 5b 40 ± 6b 19 ± 5b Adult group 5 0.75 89 ± 4 78 ± 3 68 ± 2 45 ± 2 20 ± 3 Infant group 4 0.81 101 ± 2 77 ± 5b 55 ± 5b 24 ± 5b 5 ± 3b

aAll glucose values expressed in mg/dL (mean± SEM), bDifference between the adult group and infant group at comparable time and

hematocrit is significant p,0.05 or less

Rebuilt from original

20 40 60 80 100 120 2 4 6 Glucose (mg/dl) Time (hours)

Glucose Changes Over Time

• umbil. cord 1
• umbil. cord 2

umbil.cord 3

• umbil. cord 4

adult adult adult adult adult

Umbilical Cord 1 y =-8.7069x + 98.638 R2 = 0.9892 Hct = 0.51 Umbilical Cord 1 y =-10.552x + 98.034 R2 = 0.99 Hct = 0.60 Umbilical Cord 1 y =-13.552x + 97.034 R2 = 0.9884 Hct = 0.71 Umbilical Cord 1 y =-15.87x + 93.664 R2 = 0.9695 Hct = 0.81 Adult 1 y =-5.319x+ 88.629 R2 = 0.9993 Hct = 0.43 Adult 2 y =-6.172x + 88.48 R2 = 0.9985 Hct = 0.51 Adult 3 y =-7.724x + 88.483 R2 = 0.9993 Hct = 0.60 Adult 4 y =-9.612x + 88.991 R2 = 0.9998 Hct = 0.68 Adult 5 y =-11.466x + 89.81 R2 = 0.9986 Hct = 0.75

Regression Lines

Rebuilt from original

y = -24.311x + 3.8169 R² = 0.9976 y = -19.347x + 3.4345 R² = 0.975

• 18
• 16
• 14
• 12
• 10
• 8
• 6
• 4
• 2

0.2 0.4 0.6 0.8 1

Slope (change in glucose/hr) Hct

Slope versus Hct

• umbil. cord blood

adult Linear (umbil. cord blood) Linear (adult)

Infant cord blood 1.35 mmol/L/hr Adult blood 1.07 mmol/L/hr

Capillary versus Venous Specimen

Capillary versus Venous Specimen

Capillary glucose can be up to 20- 25% higher than venous glucose

Capillary versus Venous Specimen

ONLY FOR A FASTING SPECIMEN !!

Sugar Confusion

Galactose Concentration (mmol/L) Reference Glucose (mmol/L) 0.2 0.4 0.6 0.8 1.0 1.2 1.4 1.0 1.0 1.10 1.15 1.20 1.26 1.31 1.37 1.44 1.5 1.5 1.62 1.69 1.75 1.82 1.89 1.96 2.04 2.0 2.0 2.14 2.21 2.29 2.37 2.45 2.53 2.62 2.5 2.5 2.65 2.73 2.81 2.90 3.00 3.08 3.18 3.0 3.0 3.15 3.24 3.33 3.43 3.52 3.62 3.72

Galactose Concentration (mmol/L) Reference Glucose (mmol/L) 0.2 0.4 0.6 0.8 1.0 1.2 1.4 1.0 1.0 1.10 1.15 1.20 1.26 1.31 1.37 1.44 1.5 1.5 1.62 1.69 1.75 1.82 1.89 1.96 2.04 2.0 2.0 2.14 2.21 2.29 2.37 2.45 2.53 2.62 2.5 2.5 2.65 2.73 2.81 2.90 3.00 3.08 3.18 3.0 3.0 3.15 3.24 3.33 3.43 3.52 3.62 3.72

18 27 36 45 54 18 27 36 45 54 19.8 29.2 38.5 47.7 56.7 20.7 30.4 39.8 49.1 58.3 21.6 31.5 41.2 50.6 59.9 22.7 32.8 42.7 52.2 61.7 23.6 34.0 44.1 54.0 63.4 24.7 35.3 45.5 55.4 65.2 25.9 36.7 47.2 57.2 67.0 mg/ dL 3.6 7.2 10.8 14.4 18.0 21.6 25.2

Effect of Low Galactose Concentrations

• n the Performance of the Nova Xpress

Glucose meter

Glucose (mmol/L) Nova Xpress Glucose (mmol/L)

1 2 3 4 1 2 3 4

0.2 mmol/L 0.4 mmol/L 0.6 mmol/L 0.8 mmol/L 1.0 mmol/L identity 1.2 mmol/L 1.4 mmol/L

Galactose Concentration (mmol/L) Reference Glucose (mmol/L) 0.2 0.4 0.6 0.8 1.0 1.2 1.4 1.0 1.0 0.99 0.99 1.00 1.00 1.00 1.00 1.00 1.5 1.5 1.49 1.49 1.49 1.50 1.50 1.50 1.50 2.0 2.0 1.98 1.99 1.99 1.99 1.99 2.00 2.00 2.5 2.5 2.48 2.48 2.48 2.49 2.49 2.49 2.50 3.0 3.0 2.97 2.98 2.98 2.98 2.99 2.99 2.99

Effect of Low Galactose Concentrations

• n the Performance of the Nova Xpress

Glucose meter

Glucose (mmol/L) Nova Xpress Glucose (mmol/L)

1 2 3 4 1 2 3 4

0.2 mmol/L 0.4 mmol/L 0.6 mmol/L 0.8 mmol/L 1.0 mmol/L identity 1.2 mmol/L 1.4 mmol/L

Galactose Concentration (mmol/L) Reference Glucose (mmol/L) 0.2 0.4 0.6 0.8 1.0 1.2 1.4 1.0 1.0 0.99 0.99 1.00 1.00 1.00 1.00 1.00 1.5 1.5 1.49 1.49 1.49 1.50 1.50 1.50 1.50 2.0 2.0 1.98 1.99 1.99 1.99 1.99 2.00 2.00 2.5 2.5 2.48 2.48 2.48 2.49 2.49 2.49 2.50 3.0 3.0 2.97 2.98 2.98 2.98 2.99 2.99 2.99

18 27 36 45 54 18 27 36 45 54 17.8 26.8 35.6 44.6 53.5 17.8 26.8 35.8 44.6 53.6 18 26.8 35.8 44.6 53.6 18 27 35.8 44.8 53.6 18 27 35.8 44.8 53.8 18 27 36 44.8 53.8 18 27 36 45 53.8 3.6 7.2 10.8 14.4 18.0 21.6 25.2 mg/ dL

Legal Consequences of Missing a Neonatal Hypoglycemia

Conclusions

• No widely accepted definition of neonatal

hypoglycemia currently exists

• Incidence of hypoglycemia for “at risk” infants is

profound

• Measurement of glucose level is complicated
• Numerous factors can influence the

measurement (tubes, temperature, length of time before specimen processing, interfering substances)